Bisphosphonates are the most common treatment for osteoporosis. In the last few years, increasing reports of osteonecrosis of the jaw (ONJ) have raised considerable concerns regarding the long-term safety of these agents. The case reports have created considerable uncertainty with patients and clinicians regarding the optimal pharmacotherapy for osteoporosis. Osteonecrosis of the jaw presents as a painful or painless area of exposed and sometimes infected bone in the oral cavity. Its morbidity, cost, and ideal treatment are not well understood. This R21 revised grant proposal will utilize the statistical power of large health care utilization databases to estimate the incidence of ONJ among users of bisphosphonates without cancer. All ONJ cases among a cohort of typical adults without cancer will be confirmed with primary chart review. Important subgroups of patients will be assessed including patients with prior dental extractions or infections, concomitant use of glucocorticoids, and specific comorbid illnesses. The clinical course and health care expenditures associated with ONJ will be assessed through chart review and analysis of the health care utilization database. Data from the confirmed cases of ONJ will form one of the largest collected case series of this condition, allowing assessment of the effectiveness of different treatment strategies for ONJ. Information from this proposal will answer immediate questions about the association between bisphosphonates and ONJ and will provide important data that can be used in designing future treatment trials for this condition. PUBLIC HEALTH RELEVANCE: The proposed research will estimate the incidence and relative risk of osteonecrosis of the jaw among bisphosphonate users with osteoporosis. Millions of Americans have osteoporosis and many of them are using bisphosphonates for this condition. Pharmacotherapy for osteoporosis may be substantially affected through a better understanding of risks associated with this group of medications.